Pharmacokinetic Drug Interactions of Commonly Used Anticancer Drugs

Abstract

With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example, the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids, such as probenecid, salicylates and penicillin, which compete for tubular secretion, resulting in delayed clearance of methotrexate. The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.

Perceptions and attitudes of clinical oncologists on complementary and alternative medicine

“…Theoretically, salicylate herbs (e.g., cramp bark, willow, wintergreen) could interact with methotrexate or similar cytotoxic drugs, decrease the excretion of those drugs, and induce increased plasma levels of those drugs. 28 The current study revealed that 84% of Japanese oncologists were concerned about interactions between anticancer drugs and CAM products and that 91.8% experienced concurrent use of anticancer drugs with CAM products. However, our present knowledge of interactions is incomplete, especially regarding anticancer drugs, and more research is needed urgently.…”

Interactions of Antineoplastic Chemotherapy with Zidovudine Pharmacokinetics in Patients with HIV-Related Neoplasms

“…At Toffoli/Errante/Corona/Vaccher/ Bertola/Robieux/Aita/Sorio/Tirelli/ Boiocchi present, the biochemical bases of the modulation of C max and T max of ZDV by chemotherapy are not clearly understood. The antineoplastic drugs could determine some effects on the gastrointestinal mucosa by affecting gastric motility, which could interfere with the kinetics of ZDV absorption, as demonstrated for other drugs [20,27]. It must be considered that Ruhnke et al [28] reported a decrease in ZDV peak after food intake as a consequence of inhibition of gastric emptying.…”

Clinical use of thymidine as a rescue agent from methotrexate toxicity

“…However, in the rare cases where the patient does develop acute renal failure from treatment, the serum levels of MTX will persist until renal function improves. Certain drug interactions may also lead to renal dysfunction and place the patient at excessive risk of toxicity [3,11,12].…”